Renal Sympathetic Activity Research Articles

Renal Denervation for Resistant Hypertension: Past, Present, and Future.

Renal denervation (RDN) for treatment of resistant hypertension was introduced only 5 years ago. A clear pathophysiological role of renal sympathetic activity for the initiation and maintenance of hypertension and promising data showing a substantial and sustained blood pressure (BP) reduction after RDN has promoted the widespread use of the method at least in Europe. However, in a pivotal trial that included a sham-control group, no significant BP lowering effects was observed. Afterwards, it became clear that methodological issues and poor performance and execution of the intervention have hampered the results of Symplicity HTN-3 study, thereby limiting its validity profoundly. Now, in 2015, the renaissance of RDN has begun and new randomized prospective clinical trials have or will be started soon. In the meantime, it may be wise not to ignore all previous findings, as a rescue therapy for treatment resistant hypertension. A new science era emerged, with changes of the interventional approach and selection of patients potentially profiting most from RDN.

Pubertal administration of antiserum against nerve growth factor regresses renal vascular remodeling in spontaneously hypertensive rats.

To investigate the role of nerve growth factor (NGF) in the development of hypertensive renal vascular remodeling, antiserum against NGF (anti-NGF) or vehicle was injected at 3 weeks of age in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats (n = 9 for each treatment in each strain). Flow-pressure (F-P) and pressure-glomerular filtration rate (P-GFR) relationships at vasodilated perfused kidneys were determined at 10 weeks of age. In the vehicle rats, blood pressure, renal noradrenaline content, the gradient of F-P (minimal vascular resistance at pre- and post-glomerular vasculature) and the X-intercept of P-GFR (preglomerular : postglomerular vascular resistance ratio) were greater in SHR than in WKY rats, although the gradient of P-GFR (glomerular filtration capacity) did not differ significantly between the strains. Blood pressure and renal noradrenaline content were lower in SHR receiving anti-NGF than in SHR receiving vehicle, although such difference was not observed in WKY rats. The gradient of F-P was less but the gradient of P-GFR was greater in SHR receiving anti-NGF compared with SHR receiving vehicle, although the similar differences did not occur in WKY rats. Blood pressure and renal noradrenaline content remained greater in SHR treated with anti-NGF compared with WKY rats treated with vehicle; however, the gradient of F-P did not differ significantly between them. Contrary, anti-NGF did not affect the X-intercept of P-GFR in either strain. In conclusion, NGF could contribute to the genesis of renal vascular remodeling, at least in part, through modification of renal sympathetic activity and blood pressure in SHR.

Autonomic modulation for the management of patients with chronic heart failure.

Dysregulation of the autonomic nervous system in heart failure (HF) has received considerable attention during the past 3 decades, largely because of the well-recognized association between increased sympathetic activity and the elaboration of biologically active molecules, collectively referred to as neurohormones, that help to maintain cardiovascular homeostasis through increased volume expansion, peripheral arterial vasoconstriction, and increased myocardial contractility. However, high and sustained levels of these biologically active molecules (eg, norepinephrine, angiotensin II, aldosterone) are overtly toxic to the heart and circulation.1 These and other insights have led to the clinical use of neurohormonal antagonists, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone antagonists, and β-blockers to treat patients with HF with a reduced left ventricular ejection fraction (LVEF).1 The effectiveness of these pharmacological agents is predominantly because of their ability to directly antagonize the deleterious effects of excessive sympathetic and renin–angiotensin activation. However, the current guideline-directed medical therapy (GDMT) in patients with HF fails to completely restore normal autonomic balance disrupted as a part of HF pathophysiology. During the last decade, a novel approach has generated widespread interest: modulation of the autonomic nervous system as a result of either a one-time intervention (eg, denervation) or of ongoing active therapy (eg, electric stimulation) as a means of further diminishing the sympathovagal imbalance that develops in HF.2,3 Of note, therapeutic neuromodulation with device-based therapies, either with spinal cord stimulation (SCS) or vagal stimulation (VS), has been used safely in patients with chronic pain, epilepsy, and depression, since the 1980s. As noted above, HF with a reduced LVEF is associated with sustained activation of the sympathetic nervous system that is accompanied by a withdrawal of parasympathetic tone. Impaired arterial baroreflexes have been proposed as an important mechanism that contributes to the sympathovagal imbalance present in HF4 …

Mechanisms of renal sympathetic activation in renovascular hypertension.

What is the topic of this review? This review addresses the underlying mechanisms involved in sympathoexcitation during renovascular hypertension, focusing on the importance of increased oxidative stress in the paraventricular nucleus and rostral ventrolateral medulla. What advances does it highlight? Whether renal or autonomic dysfunction is the major contributor to systemic hypertension following a renovascular insult is still a matter of debate. Here, we take an integrative approach by describing the crosstalk between the kidney and brain. We show how changes in the CNS, and in sympathetic premotor neurons in particular, are activated by ischaemic renal disease in an experimental model of renovascular hypertension. This review addresses the underlying mechanisms involved in the sympathoexcitation in renovascular hypertension. We focus on the importance of increased oxidative stress in the paraventricular nucleus of hypothalamus (PVN) and rostral ventrolateral medulla (RVLM) for the autonomic dysfunction associated with renovascular hypertension in the two-kidney, one-clip (2K-1C) model. We found in 2K-1C rats, 6weeks after clipping, a significant increase in the mRNA and protein expression of the angiotensinII type1 receptor within the RVLM and PVN. In addition, mRNA from NADPH oxidase subunits (p47phox and gp91phox) was greater in the RVLM and PVN of 2K-1C rats than in a sham-operated group. However, CuZn superoxide dismutase gene expression in these regions was not changed, suggesting that excessive production of reactive oxygen species overwhelms any endogenous antioxidant system in the RVLM and PVN in renovascular hypertension. In fact, acute administration of tempol or vitaminC (either i.v. or directly into the PVN or RVLM) caused a significant decrease in blood pressure and renal sympathetic nerve activity in 2K-1C rats, but not in control animals. Thus, we suggest that an increase in the activity of RVLM and PVN neurons triggered by angiotensinII and oxidative stress is a major mechanism involved in the maintenance of sympathoexcitation of the cardiovascular system in renovascular hypertension.

Combining drugs to optimize the therapy of hypertension: experimental evidence derived from animal models

Hypertension is widely known to promote renal disease and this is associated with complex pathophysiological mechanisms including enhanced renal sympathetic activity and the hyperactivation of the renin–angiotensin–aldosterone system (RAAS). Increased sympathetic nervous system stimulation activates renin release, sodium reabsorption, vasoconstriction, and decreased renal blood flow.1 Abnormal activation of the RAAS and increased renin secretion lead to increased angiotensin II production, which in turn activates multiple intracellular signaling pathways (Figure 1) that result in increased blood pressure and a variety of functional and structural alterations of the cardiovascular system.2

Clinical Implications

HomeHypertensionVol. 65, No. 4Clinical Implications Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBClinical Implications Originally published1 Apr 2015https://doi.org/10.1161/HYPERTENSIONAHA.115.05374Hypertension. 2015;65:697Renal Denervation and Atherosclerosis (page 758)Sympathetic nervous system overactivity is associated with a variety of cardiovascular diseases. Sympathetic innervation to specific organs may be particularly relevant. For example, renal sympathetic activity may play an important role in hypertension by regulating renin–angiotensin–aldosterone system activity, as well as other humoral factors. These downstream factors may also affect other vascular disease processes, such as atherosclerosis, independent of hypertension. In this issue of Hypertension, Wang et al report the effects of renal denervation (RDN) in a normotensive, atherosclerosis-prone mouse model. Despite absence of effects on blood pressure or total cholesterol, mice receiving bilateral RDN developed less atherosclerosis compared with mice receiving a sham operation (Figure). Atherosclerotic lesions in RDN mice also appeared more stable with increased smooth muscle cell content. Protection from atherosclerosis in the RDN group was associated with reduction of systemic factors implicated in the progression of atherosclerosis, including aldosterone, monocyte chemoattractant protein-1, and a marker of oxidative stress, 8-isoprostane. Further studies will be necessary to identify the precise causal mechanism(s) responsible for the apparent beneficial effects of RDN on progression of atherosclerosis, so that this pathway might be targeted in subjects at high risk for vascular disease. Complications of atherosclerosis (or surrogate end points) should also be studied if future clinical RDN trials in humans are performed.Download figureDownload PowerPointPreeclampsia Potentiates Future Vascular Injury (page 863)Download figureDownload PowerPointWomen who develop preeclampsia during pregnancy have an increased risk of cardiovascular disease later in life. Preeclampsia affects 5% of pregnancies, thereby exposing many women to increased cardiovascular risk for which there is no treatment aside from modification of traditional risk factors. The pervading explanation for this 2- to 4-fold increased cardiovascular risk is that preeclampsia identifies woman destined to develop cardiovascular disease. This is based on data revealing common risk factors for preeclampsia and cardiovascular disease. In this issue of Hypertension, Pruthi et al provide data supporting a novel emerging theory in which permanent vascular damage sustained during the preeclamptic episode contributes directly to cardiovascular disease pathogenesis. They demonstrate for the first time that mice exposed to experimental preeclampsia retain an enhanced response to vascular injury months after preeclampsia resolves. In their study, mice without preexisting cardiovascular risk factors were exposed to wire carotid injury 2 months after experimental preeclampsia. Preeclampsia-exposed mice developed increased vessel thickening and enhanced vascular cell proliferation and fibrosis after injury. Exploration of the mechanism for these persistent changes in the vasculature after preeclampsia has the potential to yield totally novel therapies to prevent this vascular damage during preeclampsia or to treat women after preeclampsia to avert the rapid progression to cardiovascular disease.Sofalcone Upregulates Heme Oxygenase-1 and Decreases Soluble fms–Like Tyrosine Kinase 1 (page 855)Preeclampsia complicates 3% to 8% of all pregnancies and is globally responsible for an estimated 60 000 maternal deaths annually and a far greater number of fetal losses. A therapeutic for preeclampsia could be a significant breakthrough, saving mothers and babies. Sadly, there is no such treatment. Solfacone is widely used as an antiulcer agent in Asia. In this issue of Hypertension, Onda et al report studies showing Solfacone has 3 different biological actions that raise the surprising possibility that it may be a treatment for preeclampsia. Preeclampsia is strongly associated with oxidative stress. The team reports Solfacone switches on a master transcription factor (Nrf2) that translocates to the nucleus and upregulates a raft of antioxidant genes. Secondly, the preeclamptic placenta produces elevated levels of soluble fms–like tyrosine kinase 1, which circulates widely, causing maternal endothelial dysfunction. Onda et al found Solfacone decreased soluble fms–like tyrosine kinase 1 secretion. Finally, circulating placental factors (including soluble fms–like tyrosine kinase 1) cause widespread endothelial dysfunction that leads to hypertension and multiple maternal organ injury. The team used several assays to show that Solfacone may protect blood vessels by decreasing endothelial dysfunction (Figure). Although there is little data on the safety of Solfacone in pregnancy, no links have been made with adverse pregnancy outcomes. Therefore, it is justifiable to proceed to clinical trials to treat women having severe preeclampsia with Solfacone where clinical options are limited.Download figureDownload PowerPoint Previous Back to top Next FiguresReferencesRelatedDetails April 2015Vol 65, Issue 4 Advertisement Article InformationMetrics © 2015 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.115.05374 Originally publishedApril 1, 2015 PDF download Advertisement

Evidence that Combined Aliskiren and L‐arginine Treatment Reverses Renovascular Hypertension in an Animal Model

Renovascular hypertension is characterized by increased renal sympathetic activity, angiotensin II, and by endothelial dysfunction. The purpose of this study was to determine the role of renal sympathetic nerve activity (RSNA) in mediating the anti-hypertensive effects of aliskiren (ALSK) and L-arginine (L-ARG) in a rat renovascular hypertension model. Hypertension was induced by clipping the right renal artery, and the following 5 groups were divided: Sham operated; 2-kidney, 1-clip (2K1C); 2K1C plus ALSK; 2K1C plus L-ARG; and 2K1C plus ALSK+ L-ARG. The systolic blood pressure (SBP) of 2K1C rats increased from 114.4±5.2 to 204±12.7 mmHg, (P< 0.05) and was only reduced by ALSK+L-ARG treatment (138.4±4.37 mmHg). The 2K1C hypertension increased the baseline RSNA (SHAM: 62.4±6.39 vs 2K1C: 97.4±8.43%). L-ARG or ALSK+L-ARG treatment significantly decreased baseline RSNA (2K1C L-ARG:70.7±2.39; 2K1C ALSK+L-ARG: 69.3±4.23%), but ALSK treatment alone did not (2K1C ALSK: 84.2±2.5%). Urinary water, Na+, Cl- and urea excretion were similar in the 2K1C L-ARG, 2K1C ALSK+L-ARG and SHAM groups. The combination of ALSK+L-ARG restored urine flow and increased the glomerular filtration rate. The nNOS expression in the non clipped kidney was significantly increased in 2K1C ALSK+L-ARG rats. In conclusion, combined ALSK+L-ARG treatment normalizes SBP and prevents renal dysfunction in 2K1C hypertensive rats, an effect that can be attributed to reduced RSNA.

Combined Aliskiren and L-arginine treatment reverses renovascular hypertension in an animal model.

Renovascular hypertension is characterized by increased renal sympathetic activity, angiotensin II and by endothelial dysfunction. The purpose of this study was to determine the role of renal sympathetic nerve activity (RSNA) in mediating the anti-hypertensive effects of aliskiren (ALSK) and L-arginine (L-ARG) in a rat renovascular hypertension model. Hypertension was induced by clipping the right renal artery, and the following five groups were divided: SHAM operated; 2-kidney, 1-clip (2K1C); 2K1C plus ALSK; 2K1C plus L-ARG; and 2K1C plus ALSK+ L-ARG. The systolic blood pressure (SBP) of 2K1C rats increased from 114.4±5.2 to 204±12.7 mm Hg (P<0.05) and was only reduced by ALSK+L-ARG treatment (138.4±4.37 mm Hg). The 2K1C hypertension increased the baseline RSNA (SHAM: 62.4±6.39 vs. 2K1C: 97.4±8.43%). L-ARG or ALSK+L-ARG treatment significantly decreased baseline RSNA (2K1C L-ARG:70.7±2.39; 2K1C ALSK+L-ARG: 69.3±4.23%), but ALSK treatment alone did not (2K1C ALSK: 84.2±2.5%). Urinary water, Na(+), Cl(-) and urea excretion were similar in the 2K1C L-ARG, 2K1C ALSK+L-ARG and SHAM groups. The combination of ALSK+L-ARG restored urine flow and increased the glomerular filtration rate. The nNOS expression in the non clipped kidney was significantly increased in 2K1C ALSK+L-ARG rats. In conclusion, combined ALSK+L-ARG treatment normalizes SBP and prevents renal dysfunction in 2K1C hypertensive rats.

Renal sympathetic nerves – what have they got to do with cardiovascular disease?

What is the topic of this review? This review examines the role played by renal sympathetic nerves in the regulation of cardiovascular function, focusing on changes that occur during the development of hypertension and heart failure. What advances does it highlight? While elevated levels of renal sympathetic activity are a feature of many cardiovascular diseases, the relationship is not straightforward, especially in the case of hypertension. This review highlights that before consideration of targeting the renal nerves in the clinical management of cardiovascular diseases it is essential that their role in the development of the disease is established. In recent years, with the development of new clinical techniques to target the renal nerves specifically, we have seen a renewed interest in the role of the renal sympathetic nerves in the development of cardiovascular diseases. In understanding the potential of renal nerve ablation for the treatment of cardiovascular disease, first the role played by these nerves in cardiovascular regulation must be determined. Elevated renal sympathetic activity not only has the potential to increase fluid retention but may also act in a feedforward manner to increase sympathetic activation further, increasing the workload of the heart and the potential for arrhythmias. Direct recordings of renal sympathetic nerve activity in animal models of hypertension and renal noradrenaline spillover levels in individual patients with hypertension have illustrated that hypertension is not always accompanied by an increase in renal sympathetic activity. Elevated renal sympathetic nerve activity is a feature of severe heart failure, but whether removal of the renal nerves then compromises the ability to maintain cardiac function when faced with a stressor such as sepsis remains unclear. Understanding when increased renal sympathetic drive is contributing to the progression of cardiovascular diseases such as hypertension and heart failure would appear to be the key to understanding when renal nerve ablation is likely to be of benefit.

Catheter-based renal denervation reduces atrial nerve sprouting and complexity of atrial fibrillation in goats.

Atrial fibrillation (AF) leads to structural and neural remodeling in the atrium, which enhances AF complexity and perpetuation. Renal denervation (RDN) can reduce renal and whole-body sympathetic activity. Aim of this study was to determine the effect of sympathetic nervous system modulation by RDN on atrial arrhythmogenesis. Eighteen goats were instrumented with an atrial endocardial pacemaker lead and a burst pacemaker. Percutaneous catheter-based RDN was performed in 8 goats (RDN-AF). Ten goats undergoing a sham procedure served as control (SHAM-AF). AF was induced and maintained by burst pacing for 6 weeks. High-resolution mapping was used to record epicardial conduction patterns of the right and left atrium. RDN reduced tyrosine hydroxylase-positive sympathetic nerve staining and resulted in lower transcardiac norepinephrine levels. This was associated with reduced expression of nerve growth factor-β, indicating less atrial nerve sprouting. Atrial endomysial fibrosis content was lower and myocyte diameter was smaller in RDN-AF. Median conduction velocity was higher (75 ± 9 versus 65 ± 10 cm/s, P = 0.02), and AF cycle length was shorter in RDN-AF compared with SHAM-AF. Left atrial AF complexity (4.8 ± 0.8 fibrillation waves/AF cycle length versus 8.5 ± 0.8 waves/AF cycle length, P = 0.001) and incidence of breakthroughs (2.0 ± 0.3 versus 4.3 ± 0.5 waves/AF cycle length, P = 0.059) were lower in RDN-AF compared with SHAM-AF. Blood pressure was normal and not significantly different between the groups. RDN reduces atrial sympathetic nerve sprouting, structural alterations, and AF complexity in goats with persistent AF, independent of changes in blood pressure.

Implications of Renal Denervation Therapy in Patients with Sleep Apnea.

Obstructive sleep apnea (OSA) syndrome is a prevalent condition characterized by repeated episodes of obstruction of the upper airway, leading to intermittent hypoxemia and important endothelial and anatomical dysfunctions that cause cardiovascular and cerebrovascular disease. The finding of the relationship between OSA and hypertension, especially resistant hypertension (RHT), has increased the interest in therapeutic strategies that affect renal sympathetic activity in these patients. The observational studies published until now demonstrated that renal denervation therapy can reduce the severity of OSA syndrome. Renal sympathetic denervation (RDN) could be a future therapeutic possibility for conditions other than RHT, such as atrial fibrillation, heart failure, obesity, and OSA syndrome, where renal sympathetic system plays an important physiological role. The aim of this review was to elucidate the implications of renal sympathetic activity in OSA syndrome.

Renal mechanisms of salt-sensitive hypertension: contribution of two steroid receptor-associated pathways.

Although salt is a major environmental factor in the development of hypertension, the degree of salt sensitivity varies widely among individuals. The mechanisms responsible for this variation remain to be elucidated. Recent studies have revealed the involvement of two important signaling pathways in renal tubules that play key roles in electrolyte balance and the maintenance of normal blood pressure: the β2-adrenergic stimulant-glucocorticoid receptor (GR)-with-no-lysine kinase (WNK)4-Na(+)-Cl(-) cotransporter pathway, which is active in distal convoluted tubule (DCT)1, and the Ras-related C3 botulinum toxin substrate (Rac)1-mineralocorticoid receptor (MR) pathway, which is active in DCT2, connecting tubules, and collecting ducts. β2-Adrenergic stimulation due to increased renal sympathetic activity in obesity- and salt-induced hypertension suppresses histone deacetylase 8 activity via cAMP/PKA signaling, increasing the accessibility of GRs to the negative GR response element in the WNK4 promoter. This results in the suppression of WNK4 transcription followed by the activation of Na(+)-Cl(-) cotransporters in the DCT and elevated Na(+) retention and blood pressure upon salt loading. Rac1 activates MRs, even in the absence of ligand binding, with this activity increased in the presence of ligand. In salt-sensitive animals, Rac1 activation due to salt loading activates MRs in DCT2, connecting tubules, and collecting ducts. Thus, GRs and MRs are independently involved in two pathways responsible for renal Na(+) handling and salt-sensitive hypertension. These findings suggest novel therapeutic targets and may lead to the development of diagnostic tools to determine salt sensitivity in hypertensive patients.

Norepinephrine stimulates the epithelial Na+ channel in cortical collecting duct cells via α2-adrenoceptors.

There is good evidence for a causal link between excessive sympathetic drive to the kidney and hypertension. We hypothesized that sympathetic regulation of tubular Na(+) absorption may occur in the aldosterone-sensitive distal nephron, where the fine tuning of renal Na(+) excretion takes place. Here, the appropriate regulation of transepithelial Na(+) transport, mediated by the amiloride-sensitive epithelial Na(+) channel (ENaC), is critical for blood pressure control. To explore a possible effect of the sympathetic transmitter norepinephrine on ENaC-mediated Na(+) transport, we performed short-circuit current (Isc) measurements on confluent mCCDcl1 murine cortical collecting duct cells. Norepinephrine caused a complex Isc response with a sustained increase of amiloride-sensitive Isc by ∼44%. This effect was concentration dependent and mediated via basolateral α2-adrenoceptors. In cells pretreated with aldosterone, the stimulatory effect of norepinephrine was reduced. Finally, we demonstrated that noradrenergic nerve fibers are present in close proximity to ENaC-expressing cells in murine kidney slices. We conclude that the sustained stimulatory effect of locally elevated norepinephrine on ENaC-mediated Na(+) absorption may contribute to the hypertensive effect of increased renal sympathetic activity.

Salt feedback on the renin-angiotensin-aldosterone system

The renin-angiotensin-aldosterone system (RAAS) is a central element in the control of the salt and water balance of the body and arterial blood pressure. The activity of the RAAS is controlled by the protease renin, which is released from renal juxtaglomerular epithelioid cells (JGE cells) into the circulation. Renin release is regulated by a complex interplay of several locally acting hormones or mechanisms and longer feedback loops one of which involves salt intake. Acute NaCl loads or longer lasting high salt intakes suppress plasma renin activity, whereas reductions in NaCl intake stimulate it. Because the activation of the RAAS conserves the salt content of the body, a classical feedback loop between salt intake/body salt content and renin is established. Despite of its important role for body fluid homeostasis, the precise signaling pathways connecting salt intake with the synthesis and release of renin are only incompletely understood. Four putative controllers of the salt-dependent regulation of the RAAS have been suggested: (1) the macula densa mechanism which adjusts renin release in response to changes in the renal tubular salt concentration; (2) salt-dependent changes in the arterial blood pressure; (3) circulating salt-dependent hormones, particularly the atrial natriuretic peptide (ANP); and (4) renal sympathetic nervous activity, which is regulated by extracellular volume and arterial blood pressure. In this review, the role of these known controllers of the RAAS will be discussed with special emphasis on their relative contributions to the salt-dependent regulation of the RAAS at different time frames.

Abstract 20189: Renal Denervation With Neuron Targeted Nanoparticles Attenuates the Hypertension Associated With Obesity

Introduction: Obesity is associated with hypertension and increased renal sympathetic nervous activity, Our recent study indicated that autonomic denervation could be induced by nanoparticles.In addition, non-toxic fragment of tetanus toxin, known as tetanus toxin C fragment(TTC), which demonstrates extremely high affinity binding to the surfaces of neurons. Hypothesis: This study was to test the hypothesis that renal denervation with TTC-conjugated nanoparticles could attenuate hypertension associated with obesity . Methods: TTC-conjugated nanoparticles and neurotoxic agent (N-isopropylacrylamide monomer) were synthesized. We determined the hemodynamic responses to a high-fat diet in control (n = 6) and renal-denervated by nanoparticles (n = 8) chronically instrumented dogs. After a control period of 7 days, dogs were placed on a high-fat diet for 5 weeks. a modified balloon catheter will be advanced in the target renal artery segment to allow nanoparticles permeating into vascular wall, after that the moving of nanoparticles will be guided by outside magnetic filed towards renal sympathetic nerve.Blood pressure(BP),heart rate variability (HRV),serum norepinephrine (NE) were measured. Pathological examinations were performed on all retrieved samples. Results: In response to a high-fat diet, body weight increased from 17.6 ± 2.4 to 24.8 ± 1.8 kg in the control group. Heart rate increased from 92 ± 6 to 118 ± 10 beats per minute in the control group. BP increased significantly from 105 ± 5 to 139 ± 4 mm Hg in the control group. In contrast, 5 weeks of a high-fat diet in the renal denervation group did not significantly increase body weight(which went from 18.3 ± 2.5 to 19 ± 2.1 mm Hg), Heart rate (which went from 87 ± 3 to 89 ± 6 mm Hg) and BP (which went from 107 ± 3 to 109 ± 6 mm Hg). sympathetic indices of HRV, serum NE, renal sympathetic activity and the expression of c-fos protein in renal sympathetic nerve was significantly lower in the renal denervation group. A histological examination revealed the disruption of nerve fibers, necrosis of Schwann cells and neurons, and apparent denervation in denervation group. Conclusions: Our results indicate that Renal denervation by TTC-conjugated nanoparticles could attenuate hypertension associated with obesity.

Excitatory amino acid receptors mediate asymmetry and lateralization in the descending cardiovascular pathways from the dorsomedial hypothalamus.

The dorsomedial hypothalamus (DMH) and lateral/dorsolateral periaqueductal gray (PAG) are anatomically and functionally connected. Both the DMH and PAG depend on glutamatergic inputs for activation. We recently reported that removal of GABA-ergic tone in the unilateral DMH produces: asymmetry, that is, a right- (R-) sided predominance in cardiac chronotropism, and lateralization, that is, a greater increase in ipsilateral renal sympathetic activity (RSNA). In the current study, we investigated whether excitatory amino acid (EAA) receptors in the DMH–PAG pathway contribute to the functional interhemispheric difference. In urethane (1.2 to 1.4 g/kg, i.p.) anesthetized rats, we observed that: (i) nanoinjections of N-methyl D-aspartate (NMDA 100 pmol/100 nl) into the unilateral DMH produced the same right-sided predominance in the control of cardiac chronotropy, (ii) nanoinjections of NMDA into the ipsilateral DMH or PAG evoked lateralized RSNA responses, and (iii) blockade of EAA receptors in the unilateral DMH attenuated the cardiovascular responses evoked by injection of NMDA into either the R- or left- (L-) PAG. In awake rats, nanoinjection of kynurenic acid (1 nmol/100 nL) into the L-DMH or R- or L-PAG attenuated the tachycardia evoked by air stress. However, the magnitude of stress-evoked tachycardia was smallest when the EAA receptors of the R-DMH were blocked. We conclude that EAA receptors contribute to the right-sided predominance in cardiac chronotropism. This interhemispheric difference that involves EAA receptors was observed in the DMH but not in the PAG.

Effects of renal denervation on atrial arrhythmogenesis.

Atrial fibrillation is the most common sustained arrhythmia and is associated with significant morbidity and mortality. In addition to mechanisms such as atrial stretch and atrial remodeling, the activity of the autonomic nervous system has also been suggested to contribute to the progression from paroxysmal to persistent atrial fibrillation. Catheter-based renal denervation was introduced as a minimally invasive approach to reduce renal and whole body sympathetic activation with accompanying blood pressure reduction and left-ventricular morphological and functional improvement in drug-resistant hypertension. This review focuses on the potential effects of renal denervation on different arrhythmogenic mechanisms in the atrium and discusses potential anti-remodeling effects in atrial fibrillation patients with hypertension, heart failure and sleep apnea.

Gastrointestinal intervention ameliorates high blood pressure through antagonizing overdrive of the sympathetic nerve in hypertensive patients and rats.

BackgroundWe investigated the hypothesis that the favorable effects of gastrointestinal (GI) intervention on hypertension (HTN) and cardiovascular (CV) disturbances are mediated by antagonizing overdrive of the sympathetic nervous system (SNS).Methods and ResultsHypertensive patients with metabolic disturbances underwent laparoscopic Roux‐en‐Y gastric bypass surgery, and spontaneously hypertensive rats (SHRs) underwent RYGB or sham surgery. Blood pressure (BP), heart rate (HR), endothelium‐dependent flow‐mediated dilation, and anthropometric as well as laboratory parameters were measured at baseline and during follow‐up. Changes of BP and HR in response to cold stress, renal sympathetic nervous activity (RSNA), vasoconstriction induced by electrical field stimulation, microinjection of nucleus of the solitary tract (NTS), and CV function and structure were examined in SHRs with or without surgery. Compared with baseline, BP and HR were significantly reduced in both hypertensive patients with type 2 diabetes and rats. Impaired endothelial‐dependent vasodilatation and metabolic disturbances in hypertensive patients were also ameliorated after surgery. CV disturbances were reversed by surgery in SHRs. Under acute cold exposure, the variations in BP and HR were smaller in surgically treated SHRs, compared to sham SHRs. RSNA and vasoconstriction induced by perivascular nerve stimulation as well as NTS‐mediated changes of BP were decreased in surgically treated SHRs, compared to sham SHR. Weight loss did not affect BP and RSNA in sham SHRs.ConclusionsGI intervention ameliorates HTN in both hypertensive patients and rats by inhibiting overdrive of the SNS. Therefore, targeting gastrointestine could be a novel strategy to treat HTN with metabolic disturbances.

Role of the Sympathetic Nervous Activity in Hypertension-Update in 2013

Many reviews focused on the role of sympathetic nervous activity in hypertension have been published. Recently a new treatment, radiofrequency renal denervation for the treatment of resistant hypertension has been developed and examined in several clinical trials such as the Symplicity HTN and EnligHTN studies. In the Symplicity HTN-1 study the efficacy for lowering blood pressure remained satisfactory at 3 years follow up and many ancillary ameliorative effects have been reported including cardiovascular, psychosocial, and metabolic effects. The purpose of this review is to provide the current findings on the relationships between sympathetic nerve activity and hypertension, especially focus on the importance of renal sympathetic nervous activity for the onset and development of hypertension. In addition, the methods to assess sympathetic nervous activity are reviewed. The renal denervastion was developed for the treatment-resistant hypertensive patients, and excessive confidence of the efficacy and safety existed by the end of 2013, although several issues on the efficacy and safety were reported in 2014. Furthermore, long-term efficacy and impact on renal function have been unclear. Those issues have to be clear for clinical usage. This review will also address the recent data from the renal denervation. Keywords: Hypertension, sympathetic nervous activity, symplicity-1 study.

Central nervous system dysfunction in obesity-induced hypertension.

The activation of the sympathetic nervous system is a major mechanism underlying both human and experimental models of obesity-related hypertension. While insulin and the adipokine leptin have long been thought to contribute to obesity-related neurogenic mechanisms, the evidence is now very strong that they play a major role, shown particularly in animal studies using selective receptor antagonists. There is not just maintenance of leptin's sympatho-excitatory actions as previously suggested but considerable amplification particularly in renal sympathetic nervous activity. Importantly, these changes are not dependent on short-term elevation or reduction in plasma leptin or insulin, but require some weeks to develop indicating a slow "neural adaptivity" within hypothalamic signalling. These effects can be carried across generations even when offspring are raised on a normal diet. A better understanding of the underlying mechanism should be a high research priority given the prevalence of obesity not just in the current population but also for future generations.